Effects of sex, age, and body mass index on serum bicarbonate.

Rationale: Obesity hypoventilation syndrome (OHS) is often underdiagnosed, with significant morbidity and mortality. Bicarbonate, as a surrogate of arterial carbon dioxide, has been proposed as a screening tool for OHS. Understanding the predictors of serum bicarbonate could provide insights into risk factors for OHS. We hypothesized that the bicarbonate levels would increase with an increase in body mass index (BMI), since the prevalence of OHS increases with obesity. Methods: We used the TriNetX Research Network, an electronic health record database with de-identified clinical data from participating healthcare organizations across the United States, to identify 93,320 adults without pulmonary or advanced renal diseases who had serum bicarbonate and BMI measurements within 6 months of each other between 2017 and 2022. We used linear regression analysis to examine the associations between bicarbonate and BMI, age, and their interactions for the entire cohort and stratified by sex. We also applied a non-linear machine learning algorithm (XGBoost) to examine the relative importance of age, BMI, sex, race/ethnicity, and obstructive sleep apnea (OSA) status on bicarbonate. Results: This cohort population was 56% women and 72% white and 80% non-Hispanic individuals, with an average (SD) age of 49.4 (17.9) years and a BMI of 29.1 (6.1) kg/m2. The mean bicarbonate was 24.8 (2.8) mmol/L, with higher levels in men (mean 25.2 mmol/L) than in women (mean 24.4 mmol/L). We found a small negative association between bicarbonate and BMI, with an expected change of -0.03 mmol/L in bicarbonate for each 1 kg/m2 increase in BMI (p < 0.001), in the entire cohort and both sexes. We found sex differences in the bicarbonate trajectory with age, with women exhibiting lower bicarbonate values than men until age 50, after which the bicarbonate levels were modestly higher. The non-linear machine learning algorithm similarly revealed that age and sex played larger roles in determining bicarbonate levels than the BMI or OSA status. Conclusion: Contrary to our hypothesis, BMI is not associated with elevated bicarbonate levels, and age modifies the impact of sex on bicarbonate.

The effect of diet-induced obesity on sleep and breathing in female mice.

Obesity and male sex are main risk factors for sleep-disordered breathing (SDB). We have shown that male diet-induced obesity (DIO) mice develop hypoventilation, sleep apnea, and sleep fragmentation. The effects of DIO on breathing and sleep architecture in females have not been investigated. We hypothesized that female mice are less susceptible to the detrimental effects of DIO on sleep and SDB compared to males. Female DIO-C57BL/6J and lean C57BL/6J mice underwent 24-hour metabolic studies and were exposed to 8% CO2 to measure the hypercapnic ventilatory response (HCVR), and sleep studies. Ventilatory response to arousals was calculated as ratio of the average and peak minute ventilation (VE) during each arousal relative to the baseline VE. Breathing stability was measured with Poincaré plots of VE. Female obesity was associated with decreased metabolism, indicated by reduced oxygen consumption (VO2) and CO2 production (VCO2). VE in 8% CO2 and HCVR were significantly attenuated during wakefulness. NREM sleep duration was reduced in DIO mice, but REM sleep was preserved. Ventilation during NREM and REM sleep was augmented compared to lean mice. Arousal frequency was similar between groups. Obesity increased the frequency of spontaneous arousals, whereas the apnea index was 4-fold reduced in DIO compared to lean mice. Obesity decreased pre- and post-apnea arousals. Obese mice had more stable breathing with reduced ventilatory response to arousals, compared to lean females. We conclude that obese female mice are protected against SDB, which appears to be related to an attenuated CO2 responsiveness, compared to the lean state.

Ketogenic diet acutely improves gas exchange and sleep apnoea in obesity hypoventilation syndrome: A non-randomized crossover study.

BACKGROUND AND OBJECTIVE: Obesity hypoventilation syndrome (OHS) causes hypercapnia which is often refractory to current therapies. We examine whether hypercapnia in OHS can be improved by a ketogenic dietary intervention. METHODS: We conducted a single-arm crossover clinical trial to examine the impact of a ketogenic diet on CO2 levels in patients with OHS. Patients were instructed to adhere to 1 week of regular diet, 2 weeks of ketogenic diet, followed by 1 week of regular diet in an ambulatory setting. Adherence was assessed with capillary ketone levels and continuous glucose monitors. At weekly visits, we measured blood gases, calorimetry, body composition, metabolic profiles, and sleep studies. Outcomes were assessed with linear mixed models. RESULTS: A total of 20 subjects completed the study. Blood ketones increased from 0.14 ± 0.08 during regular diet to 1.99 ± 1.11 mmol/L (p < 0.001) after 2 weeks of ketogenic diet. Ketogenic diet decreased venous CO2 by 3.0 mm Hg (p = 0.008), bicarbonate by 1.8 mmol/L (p = 0.001), and weight by 3.4 kg (p < 0.001). Sleep apnoea severity and nocturnal oxygen levels significantly improved. Ketogenic diet lowered respiratory quotient, fat mass, body water, glucose, insulin, triglycerides, leptin, and insulin-like growth factor 1. Rebound hypercapnia was observed after resuming regular diet. CO2 lowering was dependent on baseline hypercapnia, and associated with circulating ketone levels and respiratory quotient. The ketogenic diet was well tolerated. CONCLUSION: This study demonstrates for the first time that a ketogenic diet may be useful for control of hypercapnia and sleep apnoea in patients with obesity hypoventilation syndrome.

Targeted Hypoglossal Nerve Stimulation for Patients With Obstructive Sleep Apnea: A Randomized Clinical Trial.

Importance: Evidence is lacking from randomized clinical trials of hypoglossal nerve stimulation in obstructive sleep apnea (OSA). Objective: To evaluate the safety and effectiveness of targeted hypoglossal nerve stimulation (THN) of the proximal hypoglossal nerve in patients with OSA. Design, Setting, and Participants: This randomized clinical trial (THN3) was conducted at 20 centers and included 138 patients with moderate to severe OSA with an apnea-hypopnea index (AHI) of 20 to 65 events per hour and body mass index (calculated as weight in kilograms divided by height in meters squared) of 35 or less. The trial was conducted from May 2015 through June 2018. Data were analyzed from January 2022 through January 2023. Intervention: Implant with THN system; randomized 2:1 to activation at month 1 (treatment) or month 4 (control). All received 11 months of THN with follow-up at months 12 and 15, respectively. Main Outcomes and Measures: Primary effectiveness end points comprised AHI and oxygen desaturation index (ODI) responder rates (RRs). Treatment responses at months 4 and 12/15 were defined as a 50% or greater reduction in AHI to 20 or less per hour and an ODI decrease of 25% or greater. Coprimary end points comprised (1) month 4 AHI and ODI RR in the treatment greater than the control group and (2) month 12/15 AHI and ODI RR in the entire cohort exceeding 50%. Secondary end points included sleep apnea severity (AHI and ODI) and patient-reported outcomes (Epworth Sleepiness Scale, Functional Outcomes of Sleep Questionnaire, and EQ-5D visual analog scale). Results: Among 138 participants, the mean (SD) age was 56 (9) years, and 19 (13.8%) were women. Month 4 THN RRs were substantially greater in those in the treatment vs control group (AHI, 52.3% vs 19.6%; ODI, 62.5% vs 41.3%, respectively) with treatment-control standardized mean differences of 0.725 (95% CI, 0.360-1.163) and 0.434 (95% CI, 0.070-0.843) for AHI and ODI RRs, respectively. Months 12/15 RRs were 42.5% and 60.4% for AHI and ODI, respectively. Improvements in AHI, ODI, Epworth Sleepiness Scale, Functional Outcomes of Sleep Questionnaire, and EQ-5D visual analog scale scores were all clinically meaningful (medium to large effect size). Two serious adverse events and 100 nonserious related adverse events were observed from the implant procedure or study protocol. Conclusions and Relevance: This randomized clinical trial found that THN demonstrated improvements in sleep apnea, sleepiness, and quality of life in patients with OSAs over an extended AHI and body mass index range without prior knowledge of pharyngeal collapse pattern. Clinically meaningful improvements in AHI and patient-reported responses compared favorably with those of distal hypoglossal nerve stimulation trials, although clinically meaningful differences were not definitive for ODI. Trial Registration: ClinicalTrials.gov Identifier: NCT02263859.

The efficacy of intranasal leptin for opioid-induced respiratory depression depends on sex and obesity state.

Introduction: Opioid-induced respiratory depression (OIRD) is the primary cause of death associated with opioids and individuals with obesity are particularly susceptible due to comorbid obstructive sleep apnea (OSA). Repeated exposure to opioids, as in the case of pain management, results in diminished therapeutic effect and/or the need for higher doses to maintain the same effect. With limited means to address the negative impact of repeated exposure it is critical to develop drugs that prevent deaths induced by opioids without reducing beneficial analgesia. Methods: We hypothesized that OIRD as a result of chronic opioid use can be attenuated by administration of IN leptin while also maintaining analgesia in both lean mice and mice with diet-induced obesity (DIO) of both sexes. To test this hypothesis, an opioid tolerance protocol was developed and a model of OIRD in mice chronically receiving morphine and tolerant to morphine analgesia was established. Subsequently, breathing was recorded by barometric plethysmography in four experimental groups: obese male, obese female, lean male, and lean female following acute administration of IN leptin. Respiratory data were complemented with measures of arterial blood gas. Operant behavioral assays were used to determine the impact of IN leptin on the analgesic efficacy of morphine. Results: Acute administration of IN leptin significantly attenuated OIRD in DIO male mice decreasing the apnea index by 58.9% and apnea time by 60.1%. In lean mice leptin was ineffective. Blood gas measures confirmed the effectiveness of IN leptin for preventing respiratory acidosis in DIO male mice. However, IN leptin was not effective in lean mice of both sexes and appeared to exacerbate acid-base disturbances in DIO female mice. Additionally, morphine caused a complete loss of temperature aversion which was not reduced by intranasal leptin indicating IN leptin does not decrease morphine analgesia. Discussion: IN leptin effectively treated OIRD in morphine-tolerant DIO male mice without impacting analgesia. In contrast, IN leptin had no effect in lean mice of either sex or DIO female mice. The arterial blood gas data were consistent with ventilatory findings showing that IN leptin reversed morphine-induced respiratory acidosis only in DIO male mice but not in other mouse groups. Finally, a hypercapnic sensitivity study revealed that IN leptin rescued minute ventilation under hypercapnic conditions only in DIO male mice, which suggests that differential responses to IN leptin are attributable to different leptin sensitivities depending on sex and the obesity status.

TRPM7 channels regulate breathing during sleep in obesity by acting peripherally in the carotid bodies.

Sleep-disordered breathing (SDB) affects over 50% of obese individuals. Exaggerated hypoxic chemoreflex is a cardinal trait of SDB in obesity. We have shown that leptin acts in the carotid bodies (CB) to augment chemoreflex and that leptin activates the transient receptor potential melastatin 7 (TRPM7) channel. However, the effect of leptin-TRPM7 signalling in CB on breathing and SDB has not been characterized in diet-induced obesity (DIO). We hypothesized that leptin acts via TRPM7 in the CB to increase chemoreflex leading to SDB in obesity. DIO mice were implanted with EEG/EMG electrodes and transfected with Leprb short hairpin RNA (shRNA) or Trpm7 shRNA vs. control shRNA in the CB area bilaterally. Mice underwent a full-polysomnography and metabolic studies at baseline and after transfection. Ventilatory responses to hypoxia and hypercapnia were assessed during wakefulness. Leprb and Trpm7 were upregulated and their promoters were demethylated in the CB of DIO mice. Leprb knockdown in the CB did not significantly affect ventilation. Trpm7 knockdown in the CB stimulated breathing during sleep in normoxia. These effects were not driven by changes in CB chemosensitivity or metabolism. Under sustained hypoxia, Trpm7 shRNA in the CB augmented ventilation during sleep, but decreased oxyhaemoglobin saturation. We conclude that the suppression of TRPM7 in the CB improved sleep-related hypoventilation and that the respiratory effects of CB TRPM7 channels in obesity are independent of leptin. TRPM7 signalling in the CB could be a therapeutic target for the treatment of obesity-related SDB. KEY POINTS: The leptin-TRPM7 axis in the carotid bodies may play an important role in the pathogenesis of sleep-disordered breathing. TRPM7 channels regulate breathing during sleep by acting peripherally in the carotid bodies. Suppression of TRPM7 signalling in the carotid bodies improves the obesity-induced hypoventilation in mice. Pharmacological blockade of TRPM7 channels in the carotid bodies could be a therapy for sleep-disordered breathing in obesity.

Diet-induced obesity leads to sleep fragmentation independently of the severity of sleep-disordered breathing.

Obesity is associated with sleep-disordered breathing (SDB) and unrefreshing sleep. Residual daytime sleepiness and sleep impairments often persist after SDB treatment in patients with obesity, which suggests an independent effect of obesity on breathing and sleep. However, examining the relationship between sleep architecture and SDB in patients with obesity is complex and can be confounded by multiple factors. The main goal of this study was to examine the relationship between obesity-related changes in sleep architecture and SDB. Sleep recordings were performed in 15 lean C57BL/6J and 17 diet-induced obesity (DIO) mice of the same genetic background. Arousals from sleep and apneas were manually scored. Respiratory arousals were classified as events associated with ≥30% drops in minute ventilation (VE) from baseline. We applied Poincaré analysis of VE during sleep to estimate breathing variability. Obesity augmented the frequency of arousals by 45% and this increase was independent of apneas. Respiratory arousals comprised only 15% of the arousals in both groups of mice. Breathing variability during non-rapid-eye-movment (NREM) sleep was significantly higher in DIO mice, but it was not associated with arousal frequency. Our results suggest that obesity induces sleep fragmentation independently of SDB severity.NEW & NOTEWORTHY Our diet-induced obesity (DIO) model reproduces sleep features of human obesity, including sleep fragmentation, increased apnea frequency, and larger breathing variability. DIO induces sleep fragmentation independently of apnea severity. Sleep fragmentation in DIO mice is mainly attributed to non-respiratory arousals. Increased breathing variability during sleep did not account for the higher arousal frequency in DIO. Our results provide a rationale to examine sleep in patients with obesity even when they are adequately treated for sleep-disordered breathing.

Obstructive sleep apnea.

Obstructive sleep apnea (OSA) is a disease that results from loss of upper airway muscle tone leading to upper airway collapse during sleep in anatomically susceptible persons, leading to recurrent periods of hypoventilation, hypoxia, and arousals from sleep. Significant clinical consequences of the disorder cover a wide spectrum and include daytime hypersomnolence, neurocognitive dysfunction, cardiovascular disease, metabolic dysfunction, respiratory failure, and pulmonary hypertension. With escalating rates of obesity a major risk factor for OSA, the public health burden from OSA and its sequalae are expected to increase, as well. In this chapter, we review the mechanisms responsible for the development of OSA and associated neurocognitive and cardiometabolic comorbidities. Emphasis is placed on the neural control of the striated muscles that control the pharyngeal passages, especially regulation of hypoglossal motoneuron activity throughout the sleep/wake cycle, the neurocognitive complications of OSA, and the therapeutic options available to treat OSA including recent pharmacotherapeutic developments.

Time Domains of Hypoxia Responses and -Omics Insights.

The ability to respond rapidly to changes in oxygen tension is critical for many forms of life. Challenges to oxygen homeostasis, specifically in the contexts of evolutionary biology and biomedicine, provide important insights into mechanisms of hypoxia adaptation and tolerance. Here we synthesize findings across varying time domains of hypoxia in terms of oxygen delivery, ranging from early animal to modern human evolution and examine the potential impacts of environmental and clinical challenges through emerging multi-omics approaches. We discuss how diverse animal species have adapted to hypoxic environments, how humans vary in their responses to hypoxia (i.e., in the context of high-altitude exposure, cardiopulmonary disease, and sleep apnea), and how findings from each of these fields inform the other and lead to promising new directions in basic and clinical hypoxia research.

Isovolemic hemodilution in chronic mountain sickness acutely worsens nocturnal oxygenation and sleep apnea severity.

STUDY OBJECTIVES: Chronic mountain sickness (CMS) is commonly observed among Andean and other highland populations. Sleep-disordered breathing (SDB) is highly prevalent at high altitude, and SDB and nocturnal hypoxemia have been observed in CMS. Phlebotomy is commonly performed to treat CMS, but it is unknown whether reducing hematocrit improves SDB. We hypothesized that isovolemic hemodilution (IVHD) in CMS would reduce SBD severity and improve sleep efficiency. METHODS: Six participants with CMS and 8 without CMS, all residents of Cerro de Pasco, Peru (altitude 4340 m), completed baseline nocturnal sleep studies. CMS participants then underwent IVHD, and nocturnal sleep studies were repeated 24-48 hours after IVHD. We analyzed sleep apnea severity, nocturnal oxygenation, and sleep quality in those with CMS relative to those without CMS, and the effects of IVHD in CMS participants. RESULTS: Participants with CMS did not have altered sleep architecture, sleep apnea severity, or nocturnal oxygenation relative to non-CMS participants. However, IVHD in CMS increased apnea-hypopnea index (40.9 ± 6.9 events/h to 61.5 ± 7.7 events/h, P = .009). IVHD increased oxyhemoglobin desaturation index (P = .008) and the percentage of sleep time spent with oxyhemoglobin saturation at or below 80% (P = .012). There was no effect of IVHD on sleep efficiency, arousal index, or sleep staging. CONCLUSIONS: In this cohort, CMS was not associated with worsened SDB or changes in sleep architecture. IVHD, a putative therapeutic option for participants with CMS, appears to worsen nocturnal oxygenation and SDB within 48 hours post-IVHD. CITATION: Sanchez-Azofra A, Villafuerte FC, DeYoung PN, et al. Isovolemic hemodilution in chronic mountain sickness acutely worsens nocturnal oxygenation and sleep apnea severity. J Clin Sleep Med. 2022;18(10):2423-2432.

Combined intermittent and sustained hypoxia is a novel and deleterious cardio-metabolic phenotype.

STUDY OBJECTIVES: Chronic obstructive pulmonary disease and obstructive sleep apnea overlap syndrome is associated with excess mortality, and outcomes are related to the degree of hypoxemia. People at high altitudes are susceptible to periodic breathing, and hypoxia at altitude is associated with cardio-metabolic dysfunction. Hypoxemia in these scenarios may be described as superimposed sustained hypoxia (SH) plus intermittent hypoxia (IH), or overlap hypoxia (OH), the effects of which have not been investigated. We aimed to characterize the cardio-metabolic consequences of OH in mice. METHODS: C57BL/6J mice were subjected to either SH (FiO2 = 0.10), IH (FiO2 = 0.21 for 12 h, and FiO2 oscillating between 0.21 and 0.06, 60 times/hour, for 12 h), OH (FiO2 = 0.13 for 12 h, and FiO2 oscillating between 0.13 and 0.06, 60 times/hour, for 12 h), or room air (RA), n = 8/group. Blood pressure and intraperitoneal glucose tolerance test were measured serially, and right ventricular systolic pressure (RVSP) was assessed. RESULTS: Systolic blood pressure transiently increased in IH and OH relative to SH and RA. RVSP did not increase in IH, but increased in SH and OH by 52% (p < .001) and 20% (p = .001). Glucose disposal worsened in IH and improved in SH, with no change in OH. Serum low- and very-low-density lipoproteins increased in OH and SH, but not in IH. Hepatic oxidative stress increased in all hypoxic groups, with the highest increase in OH. CONCLUSIONS: OH may represent a unique and deleterious cardio-metabolic stimulus, causing systemic and pulmonary hypertension, and without protective metabolic effects characteristic of SH.

Leptin Receptor Blockade Attenuates Hypertension, but Does Not Affect Ventilatory Response to Hypoxia in a Model of Polygenic Obesity.

BACKGROUND: Obesity can cause hypertension and exacerbates sleep-disordered breathing (SDB). Leptin is an adipocyte-produced hormone, which increases metabolic rate, suppresses appetite, modulates control of breathing, and increases blood pressure. Obese individuals with high circulating levels of leptin are resistant to metabolic and respiratory effects of leptin, but they appear to be sensitive to hypertensive effects of this hormone. Obesity-induced hypertension has been associated with hyperleptinemia. New Zealand obese (NZO) mice, a model of polygenic obesity, have high levels of circulating leptin and hypertension, and are prone to develop SDB, similarly to human obesity. We hypothesize that systemic leptin receptor blocker Allo-aca will treat hypertension in NZO mice without any effect on body weight, food intake, or breathing. METHODS: Male NZO mice, 12-13 weeks of age, were treated with Allo-aca (n = 6) or a control peptide Gly11 (n = 12) for 8 consecutive days. Doses of 0.2 mg/kg were administered subcutaneously 2×/day, at 10 AM and 6 PM. Blood pressure was measured by telemetry for 48 h before and during peptide infusion. Ventilation was assessed by whole-body barometric plethysmography, control of breathing was examined by assessing the hypoxic ventilatory response (HVR), and polysomnography was performed during light-phase at baseline and during treatment. Heart rate variability analyses were performed to estimate the cardiac autonomic balance. RESULTS: Systemic leptin receptor blockade with Allo-aca did not affect body weight, body temperature, and food intake in NZO mice. Plasma levels of leptin did not change after the treatment with either Allo-aca or the control peptide Gy11. NZO mice were hypertensive at baseline and leptin receptor blocker Allo-aca significantly reduced the mean arterial pressure from 134.9 ± 3.1 to 124.9 ± 5.7 mmHg during the light phase (P < 0.05), whereas the control peptide had no effect. Leptin receptor blockade did not change the heart rate or cardiac autonomic balance. Allo-aca did not affect minute ventilation under normoxic or hypoxic conditions and HVR. Ventilation, apnea index, and oxygen desaturation during NREM and REM sleep did not change with leptin receptor blockade. CONCLUSION: Systemic leptin receptor blockade attenuates hypertension in NZO mice, but does not exacerbate obesity and SDB. Thus, leptin receptor blockade represents a potential pharmacotherapy for obesity-associated hypertension.

Effects of Dinner Timing on Sleep Stage Distribution and EEG Power Spectrum in Healthy Volunteers.

PURPOSE: Eating time and sleep habits are important modifiable behaviors that affect metabolic health, but the relationship between food intake and sleep remains incompletely understood. Observational data suggest that late food intake is associated with impaired sleep quality. We examined the effect of routine dinner (RD, 5 hours before bedtime) vs late dinner (LD, 1 hour before bedtime) on sleep architecture in healthy volunteers. PARTICIPANTS AND METHODS: This was a post hoc analysis of a randomized crossover study of RD vs LD with a fixed sleep opportunity in a laboratory setting. On each of the two visits, 20 healthy adult volunteers (10 women) received an isocaloric meal followed by overnight polysomnography. Sleep architecture over the course of the night was assessed using visual sleep staging and EEG spectral power analysis and was compared between RD and LD. We modeled the proportions of spectral power in alpha, beta, delta, and theta bands as functions of dinner timing, time of night, and their interaction with mixed-effect spline regression. RESULTS: Conventional sleep stages were similar between the 2 visits. LD caused a 2.5% initial increase in delta power and a reciprocal 2.7% decrease in combined alpha and beta power (p<0.0001). These effects diminished as sleep continued with a reversal of these patterns in the latter part of the night. CONCLUSION: Contrary to the existing literature, shifting dinner timing from 5 hours before sleep to 1 hour before sleep in healthy volunteers did not result in significant adverse changes in overnight sleep architecture. In fact, LD was associated with deeper sleep in the beginning of the night and lighter sleep in the latter part of the night in healthy volunteers. This novel manifestation of postprandial hypersomnia may have therapeutic potential in patients with sleep disorders.

Acute Altitude Acclimatization in Young Healthy Volunteers: Nocturnal Oxygenation Increases Over Time, Whereas Periodic Breathing Persists.

Ju, Jia-Der, Cristian Zhang, Francis P. Sgambati, Lidia M. Lopez, Luu V. Pham, Alan R. Schwartz, and Roberto A. Accinelli. Acute altitude acclimatization in young healthy volunteers: nocturnal oxygenation increases over time whereas periodic breathing persists. High Alt Med Biol. 22:14-23, 2021. Study Objectives: This study aimed to examine the acute effects of high altitude (HA) on sleep disordered breathing (sleep apnea and nocturnal hypoxemia) and acute mountain sickness and to characterize acclimatization over time. Methods: Ten native lowlanders residing at sea level (SL) completed the Lake Louise Score (LLS) and underwent nocturnal polygraphy (ApneaLink Plus) for nine consecutive nights (N1-N9) at HA (2,761 m) and two nights before and after HA. Nocturnal oxygen profiles were assessed by measuring the mean nocturnal oxyhemoglobin saturation (SpO2) during sleep, and sleep apnea severity as assessed by measuring the Apnea-Hypopnea Index (AHI). Mixed-effects linear regression was used to model responses in outcomes (mean nocturnal SpO2, logAHI, and LLS) between HA and SL. Changes in SpO2 and AHI were examined in subgroups with mild versus marked nocturnal SpO2 and low versus high AHI during exposure to HA and compared between subgroups. Results: Compared with SL, the mean nocturnal SpO2 was lower (p < 0.0001) and AHI was higher (p < 0.0001) at HA. The mean nocturnal SpO2 increased progressively (p < 0.001), whereas AHI remained high (p < 0.978) and relatively unchanged over nine successive nights at HA. Those with markedly reduced SpO2 upon arrival at HA exhibited progressive increases in the mean nocturnal SpO2 over time at HA compared with those with mild nocturnal desaturation. LLS rose at HA, but no differences were observed between subgroups. Conclusions: In healthy HA sojourners, the mean nocturnal SpO2 increased progressively over time, whereas AHI remained elevated, suggesting distinctive phenotypes and acclimatization responses to HA.

Metabolic Effects of Late Dinner in Healthy Volunteers-A Randomized Crossover Clinical Trial.

CONTEXT: Consuming calories later in the day is associated with obesity and metabolic syndrome. We hypothesized that eating a late dinner alters substrate metabolism during sleep in a manner that promotes obesity. OBJECTIVE: The objective of this work is to examine the impact of late dinner on nocturnal metabolism in healthy volunteers. DESIGN AND SETTING: This is a randomized crossover trial of late dinner (LD, 22:00) vs routine dinner (RD, 18:00), with a fixed sleep period (23:00-07:00) in a laboratory setting. PARTICIPANTS: Participants comprised 20 healthy volunteers (10 male, 10 female), age 26.0 ± 0.6 years, body mass index 23.2 ±â€…0.7 kg/m2, accustomed to a bedtime between 22:00 and 01:00. INTERVENTIONS: An isocaloric macronutrient diet was administered on both visits. Dinner (35% daily kcal, 50% carbohydrate, 35% fat) with an oral lipid tracer ([2H31] palmitate, 15 mg/kg) was given at 18:00 with RD and 22:00 with LD. MAIN OUTCOME MEASURES: Measurements included nocturnal and next-morning hourly plasma glucose, insulin, triglycerides, free fatty acids (FFAs), cortisol, dietary fatty acid oxidation, and overnight polysomnography. RESULTS: LD caused a 4-hour shift in the postprandial period, overlapping with the sleep phase. Independent of this shift, the postprandial period following LD was characterized by higher glucose, a triglyceride peak delay, and lower FFA and dietary fatty acid oxidation. LD did not affect sleep architecture, but increased plasma cortisol. These metabolic changes were most pronounced in habitual earlier sleepers determined by actigraphy monitoring. CONCLUSION: LD induces nocturnal glucose intolerance, and reduces fatty acid oxidation and mobilization, particularly in earlier sleepers. These effects might promote obesity if they recur chronically.

Brief digital sleep questionnaire powered by machine learning prediction models identifies common sleep disorders.

INTRODUCTION: We developed and validated an abbreviated Digital Sleep Questionnaire (DSQ) to identify common societal sleep disturbances including insomnia, delayed sleep phase syndrome (DSPS), insufficient sleep syndrome (ISS), and risk for obstructive sleep apnea (OSA). METHODS: The DSQ was administered to 3799 community volunteers, of which 2113 were eligible and consented to the study. Of those, 247 were interviewed by expert sleep physicians, who diagnosed ≤2 sleep disorders. Machine Learning (ML) trained and validated separate models for each diagnosis. Regularized linear models generated 15-200 features to optimize diagnostic prediction. Models were trained with five-fold cross-validation (repeated five times), followed by robust validation testing. ElasticNet models were used to classify true positives and negatives; bootstrapping optimized probability thresholds to generate sensitivities, specificities, accuracies, and area under the receiver operating curve (AUC). RESULTS: Compared to reference subgroups, physician-diagnosed sleep disorders were marked by DSQ evidence of sleeplessness (insomnia, DSPS, OSA), sleep debt (DSPS, ISS), airway obstruction during sleep (OSA), blunted circadian variability in alertness (DSPS), sleepiness (DSPS and ISS), increased alertness (insomnia) and global impairment in sleep-related quality of life (all sleep disorders). ElasticNet models validated each diagnosis with high sensitivity (80-83%), acceptable specificity (63-69%), high AUC (0.80-0.85) and good accuracy (agreement with physician diagnoses, 68-73%). DISCUSSION: A brief DSQ readily engaged and efficiently screened a large population for common sleep disorders. Powered by ML, the DSQ can accurately classify sleep disturbances, demonstrating the potential for improving the sleep, health, productivity and safety of populations.